Arginine vasopressin (AVP) is a peptide consisting of 9 amino acids which is biosynthesized and secreted in the hypothalamo-pituitary system. The receptor of AVP is classified into three subtypes V1a, V1b and V2, and a V1a receptor-mediated constriction action and a V2 receptor-mediated antidiuretic action are known as the main pharmacological actions of AVP in the peripheral system. As a V2 receptor-selective agonist, a peptide desmopressin (prepared by deleting amino group of the 1-position cysteine of AVP, and converting the 8-position arginine into d form) has been synthesized and used for the treatment of central diabetes insipidus (Non-patent Reference 1). However, since bioavailability of oral preparations of desmopressin is considerably low, a high dose is necessary for obtaining its effect. Thus, the desmopressin preparations are expensive, and generation of side effects based on the variation of absorption among individuals is observed in some cases. Accordingly, concern has been directed toward the development of a non-peptide antidiuretic agent which selectively stimulates V2 receptor and has high bioavailability.
On the other hand, accompanied by the diversification of medical treatment and advance of age, single use of a drug became rather rare, and in many cases, two or more drugs are administered simultaneously or intermittently. This is the same in the field of AVP receptor agonists. Drugs are inactivated and converted into metabolites by undergoing the action of drug metabolizing enzymes, and the most important among these drug metabolizing enzymes is cytochrome P450 (CYP). A large number of molecular species exists in CYP, and when two or more drugs which are metabolized by CYP of the same molecular species compete on the metabolizing enzyme, it is considered that they undergo a certain metabolic inhibition, though it varies depending on the affinity of the drugs for CYP. As a result, increase of blood concentration, prolongation of blood half-life and the like drug interactions are expressed.
Such drug interactions are undesirable actions except for the case in which they are used aiming at the additive action or synergistic action, because they sometimes cause unexpected side effects. Thus, concern has been directed toward the creation of a medicament which has a low affinity for CYP and a small possibility of causing drug interactions.
Up to now, tricyclic compounds represented by a general formula (A), a general formula (B) and a general formula (C) are known as non-peptide compounds which are V2 receptor-selective agonists and show antidiuretic action (Patent Reference 1, Patent Reference 2, Patent Reference 3).
(See said patent references for signs in the formulae.)
Also, a condensed azepine derivative represented by a general formula (D) is known as a V2 receptor-selective agonist (Patent Reference 4).
(See said patent reference for signs in the formula.)
In addition, benzazepine derivatives represented by a general formula (E) (Patent Reference 5, Patent Reference 6) and benzo-hetero ring compounds represented by a general formula (F) or a general formula (G) (Patent Reference 7, Patent Reference 8, Patent Reference 9) are known as V2 receptor-selective agonists.
(See said patent references for signs in the formulae.)
However, there is no description in any of these patent references regarding the 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative of the invention.
Also, though 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative having antagonism for the AVP receptor or oxytocin receptor are known, nothing is known about their relation to V2 receptor agonistic action, central diabetes insipidus and nocturia (Patent Reference 10, Patent Reference 11, Patent Reference 12). In this connection, Patent Reference 10 and Patent Reference 12 does not disclose the 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative of the invention in which CF3 or halogen is substituted to the 2-position benzoyl substituting on the 1-position of benzazepine. In addition, Patent Reference 11 discloses only a compound in which an aromatic ring is directly bonded to a heteroaryl group bonding to the carbonyl substituting on the 1-position of benzazepine, but does not disclose the 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative of the invention in which the ring bonding to the carbonyl substituting on the 1-position of benzazepine has —O—, —S—, —NH— or a substituent group containing —N(lower alkyl)-.
Under such a situation, great concern has been directed toward the development of a non-peptide antidiuretic agent having high bioavailability, for the purpose of treating central diabetes insipidus and/or nocturia.
[Non-patent Reference 1] Journal of Japan Endocrine Society, 54, 676-691,
[Patent Reference 1] International Publication No. 99/06409
[Patent Reference 2] International Publication No. 99/06403
[Patent Reference 3] International Publication No. 00/46224
[Patent Reference 4] International Publication No. 01/49682
[Patent Reference 5] International Publication No. 97/22591
[Patent Reference 6] Japanese Patent No. 2926335
[Patent Reference 7] Japanese Patent No. 3215910
[Patent Reference 8] Japanese Patent publication JP-A-11-349570
[Patent Reference 9] Japanese Patent publication JP-A-2000-351768
[Patent Reference 10] International Publication No. 95/06035
[Patent Reference 11] International Publication No. 98/39325
[Patent Reference 12] Japanese Patent publication JP-A-9-221475